Alternative titles; symbols
HGNC Approved Gene Symbol: POLR3A
SNOMEDCT: 238874008, 721846006; ICD10CM: G11.5;
Cytogenetic location: 10q22.3 Genomic coordinates (GRCh38): 10:77,975,149-78,029,515 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.3 | Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism | 607694 | Autosomal recessive | 3 |
| Wiedemann-Rautenstrauch syndrome | 264090 | Autosomal recessive | 3 |
POLR3A is the largest subunit of RNA polymerase III. RNA polymerase III is a DNA-directed RNA polymerase (EC 2.7.7.6) that transcribes genes encoding ribosomal 5S RNA (180420), tRNAs, U6 small nuclear RNA (see 180692), mitochondrial RNA-processing RNA (RMRP; 157660), H1 RNA (RPPH1; 608513), Y RNAs (see 601821), and 7SK RNA (RN7SK; 606515) (summary by Sepehri and Hernandez, 1997). Pol III can also act as a DNA sensor and induces the expression of interferons (IFN) when stimulated by AT-rich DNA, which is present in certain viruses, including varicella zoster virus (VZV) and cytomegalovirus (CMV) (Ogunjimi et al., 2017).
By PCR using primers based on sequences conserved in RNA polymerase III large subunits in lower organisms, followed by screening a human NTera2D1 teratocarcinoma cell cDNA library and 5-prime RACE of total HeLa cell RNA, Sepehri and Hernandez (1997) cloned POLR3A, which they called RPC155. The deduced 1,391-amino acid protein has a calculated molecular mass of 154.7 kD. It contains a zinc-binding domain, a helix-turn-helix motif, a magnesium-binding site, and 8 regions that are conserved in RNA polymerase large subunits. RPC155 shares 50% and 40% amino acid identity with the large subunits of S. cerevisiae and T. brucei RNA polymerase III, respectively, but it shares only 32% identity with the large subunit of human RNA polymerase II (POLR2A; 180660).
Hartz (2011) mapped the POLR3A gene to chromosome 10q22.3 based on an alignment of the POLR3A sequence (GenBank AF021351) with the genomic sequence (GRCh37).
Sepehri and Hernandez (1997) found that in vitro transcribed and translated RPC115 showed significant RNA polymerase III activity in a nonspecific transcription assay. Depletion of RPC155 with neutralizing antibodies inhibited transcription from an RNA polymerase III promoter, but not from an RNA polymerase II promoter.
RNA polymerase II, which is responsible for protein-coding mRNA synthesis, binds many regions not actively transcribed owing to stalled polymerase activity, alternate transcription start sites, and regulated alternative splicing. However, by sequencing transcripts in mouse liver, Kutter et al. (2011) showed that every tRNA gene bound by RNA polymerase III was expressed. Conversely, few RNA transcripts aligned to predicted tRNA loci that were not bound by RNA polymerase III. Differential expression of tRNAs in mouse muscle, testis, and liver was determined by differential RNA polymerase III binding.
Hypomyelinating Leukodystrophy 7 with or without Oligodontia and/or Hypogonadotropic Hypogonadism
By narrowing the candidate disease locus followed by direct sequencing of genes in the refined 2.99-Mb interval in several families with hypomyelinating leukodystrophy-7 with or without oligodontia and/or hypogonadotropic hypogonadism (HLD7; 607694), Bernard et al. (2011) identified 14 different mutations in the POLR3A gene (see, e.g., 614258.0001-614258.0005). All mutations were in homozygous or compound heterozygous state, and no patient had 2 truncating mutations. There were 19 patients from 12 families, including those reported by Atrouni et al. (2003), Timmons et al. (2006), and Bernard et al. (2010). The mutations were spread throughout the gene, and there were no obvious genotype/phenotype correlations. Immunoblot analysis showed decreased levels of POLR3A protein in fibroblasts from 4 affected individuals, and decreased levels in the cortex and cerebral white matter of another patient, suggesting that loss of protein function is responsible for the disorder. Bernard et al. (2011) hypothesized that POLR3A mutations lead to dysregulation of RNA polymerase III and its targets, resulting in decreased expression of certain tRNAs during development and impaired protein synthesis.
Saitsu et al. (2011) reported a 17-year-old Japanese boy with HLD7 without oligodontia or hypogonadism caused by compound heterozygous mutations in the POLR3A gene (614258.0006 and 614258.0007).
Wiedemann-Rautenstrauch Syndrome
In a female infant with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Jay et al. (2016) identified compound heterozygosity for a splice site (614258.0002) and a nonsense mutation (R873X; 614258.0008) in the POLR3A gene. The mutations segregated with disease in the family and were not found in controls or public variant databases.
Paolacci et al. (2018) studied 15 patients from 12 families with WDRTS and identified compound heterozygous POLR3A variants in affected individuals from 8 families (see, e.g., 614258.0002, 614258.0004, and 614258.0009-614258.0016). Monoallelic variants were detected in the 4 remaining patients, but lack of genetic material precluded further analyses.
In 7 unrelated patients with WDRTS, Wambach et al. (2018) identified compound heterozygosity for mutations in the POLR3A gene (see, e.g., 614258.0004, 614258.0010, 614258.0014, 614258.0015, 614258.0017, and 614258.0018).
Somatic Mutation
In scleroderma (181750), patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, Joseph et al. (2014) hypothesized that the 'foreign' antigens in this autoimmune disease are encoded by somatically mutated genes in the patients' incipient cancers. Studying cancers from scleroderma patients, Joseph et al. (2014) found genetic alterations of the POLR3A locus in 6 of 8 patients with antibodies to RPC1, but not in 8 patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. Joseph et al. (2014) concluded that these results offered insight into the pathogenesis of scleroderma and provided support for the idea that acquired immunity helps to control naturally occurring cancers.
Susceptibility To Severe Varicella Infection
In a 5-year-old Belgian boy (P2) with a severe varicella zoster virus (VZV) infection manifest as cerebellitis with ataxia and nystagmus, Ogunjimi et al. (2017) identified a heterozygous missense variant (M307V) in the POLR3A gene. Two additional unrelated children with severe VZV manifest as pneumonitis (P3) and encephalitis (P4) were found to carry heterozygous missense variants in both the POLR3A and POLR3C (617454) genes, consistent with digenic inheritance. P3 carried a heterozygous Q707R variant in the POLR3A gene and an R438G variant in the POLR3C gene, and P4 carried an R437Q variant in the POLR3A gene and an R84Q variant in the POLR3C gene. Segregation studies were consistent with incomplete penetrance. Patient peripheral blood cells showed variably impaired interferon production when exposed to AT-rich DNA or VZV, as well as variably impaired control of VZV viral replication. The authors suggested that the variants may lead to functional defects in the Pol III DNA sensing system and impaired ability to convert AT-rich DNA into the immunostimulatory RNA pathogen-associated molecular pattern (PAMP). The patients were part of a cohort of 21 children with severe VZV infection who underwent whole-exome sequencing; the variants were confirmed by Sanger sequencing.
In 5 affected members of 3 French Canadian families with hypomyelinating leukodystrophy-7 (HLD7; 607694), Bernard et al. (2011) identified a homozygous 2015G-A transition in the POLR3A gene, resulting in a gly672-to-glu (G672E) substitution. The mutation was not found in more than 250 control chromosomes. The families were originally reported by Bernard et al. (2010) as having a disorder termed 'tremor-ataxia with central hypomyelination (TACH).' All had mild cognitive regression, upper motor neuron signs, tremor, and cerebellar signs. Two also had hypodontia, 2 others also had hypogonadotropic hypogonadism, and the fifth had neither of these additional features.
In affected members of a consanguineous Syrian family (family X) with hypomyelinating leukodystrophy-7 (HLD7; 607694), originally reported by Atrouni et al. (2003), Bernard et al. (2011) identified homozygosity for a c.2003+18G-A transition (c.2003+18G-A, NM_007055.3) in intron 14 of the POLR3A gene, resulting in the retention of 19 nucleotides from intron 14, the addition of 6 amino acids to the protein, and a premature stop codon at position 650 (referred to by the authors as Tyr637CysfsTer650). The mutation was not found in more than 250 control chromosomes. All had cognitive regression, upper motor neuron signs, cerebellar signs, and hypodontia, but none had hypogonadotropic hypogonadism.
In a female infant who died at age 7 months with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Jay et al. (2016) identified compound heterozygosity for a c.1909+18G-A mutation in intron 14 of the POLR3A gene, which was predicted to create a cryptic donor site, and a c.2617C-T transition in exon 20, resulting in an arg873-to-ter (R873X; 614258.0008) substitution. Her unaffected parents were each heterozygous for 1 of the mutations. The authors stated that the splice site mutation was not found in the Exome Variant Server or dbSNP databases, and the nonsense mutation was not reported in the ExAC database.
In a girl who died at age 10 years with WDRTS (WRS001), originally reported by Paolacci et al. (2017), Paolacci et al. (2018) identified compound heterozygosity for the c.1909+18G-A mutation (c.1909+18G-A, chr10.79769277, GRCh37) in POLR3A and a c.3206G-A transition, resulting in an arg1069-to-gln (R1069Q; 614258.0009) substitution at a highly conserved residue. The missense variant was present at very low frequency (0.002%) in the gnomAD database, whereas the splicing mutation was not found in gnomAD.
In 4 patients from 2 unrelated families (families V and VIII) with hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (HLD7; 607694), originally reported by Timmons et al. (2006), Bernard et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3A gene: a c.2554A-G transition (c.2554A-G, NM_007055.3) resulting in a met852-to-val (M852V) substitution, and a G-to-A transition in intron 19 (c.2617-1G-A; 614258.0004), predicted to remove an acceptor site, lead to the use of a cryptic acceptor site located in exon 20, and cause a premature stop codon at position 878 (referred to by the authors as Arg873AlafsTer878). All had cognitive regression, abnormal eye movements, upper motor neuron signs, cerebellar signs, hypodontia, and hypogonadotropic hypogonadism. Bernard et al. (2011) also found that a patient (individual 18 of family XI) with leukodystrophy and oligodontia was compound heterozygous for M852V and a 418C-T transition in the POLR3A gene, resulting in an arg140-to-ter (R140X; 614258.0005) substitution. None of the mutations was found in more than 250 control chromosomes.
For discussion of the splice site mutation in the POLR3A gene (c.2617-1G-A, NM_007055.3), predicted to result in use of a cryptic acceptor site and premature termination (Arg873AlafsTer878), that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (HLD7; 607964) by Bernard et al. (2011), see 614258.0003.
For discussion of the c.2617-1G-A splice site mutation (c.2617-1G-A, chr10.79753126) in the POLR3A gene, which was also found in compound heterozygous state in a 21-year-old woman (WRS005) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010.
For discussion of the c.2617-1G-A splice site mutation (c.2617-1G-A, NM_007055.3) in POLR3A, which was found in compound heterozygosity in a 21-year-old woman (subject 6) with WDRTS by Wambach et al. (2018), see 614258.0010.
For discussion of the arg140-to-ter (R140X) mutation in the POLR3A gene, resulting from a c.418C-T transition (c.418C-T, NM_007055.3) that was found in compound heterozygous state in a patient with leukodystrophy and oligodontia (HLD7; 607964) by Bernard et al. (2011), see 614258.0003.
In a 17-year-old Japanese boy (individual 4) with hypomyelinating leukodystrophy-7 (HLD7; 607694), Saitsu et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3A gene: a paternally inherited c.2690T-A transversion (c.2690T-A, NM_007055.3) in exon 20, resulting in an ile897-to-asn (I897N) substitution, and a maternally inherited c.3013C-T transition in exon 23, resulting in an arg1005-to-cys (R1005C; 614258.0007) substitution. Structural modeling using the homologous yeast pol II subunit suggested that the mutations would disturb subunit interaction, leading to loss of pol III function. Neither mutation was found in 540 Japanese control chromosomes. The patient showed normal development until age 4, when mild tremors were noted. He later developed cerebellar signs, including expressive ataxic speech, intention tremor, poor finger-to-nose test, dysdiadochokinesis, dysmetria, and wide-based ataxic gait. He also showed intellectual disability with an IQ of 57. Other features included severe myopia and unilateral sensorineural deafness. The motor deterioration was progressive, and he became wheelchair-bound around age 14 years. Brain MRI showed a hypoplastic corpus callosum, cerebellar atrophy, and white matter lesions in the basal ganglia. He did not have hypodontia or hypogonadism.
For discussion of the arg1005-to-cys (R1005C) mutation in the POLR3A gene, resulting from a c.3013C-T transition (c.3013C-T, NM_007055.3) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-7 (HLD7; 607694) by Saitsu et al. (2011), see 614258.0006.
For discussion of the c.2617C-T transition in exon 20 of the POLR3A gene, resulting in an arg873-to-ter (R873X) substitution, that was found in compound heterozygous state in a female infant with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Jay et al. (2016), see 614258.0002.
For discussion of the c.3206G-A transition (c.3206G-A, chr10.79744964, GRCh37) in the POLR3A gene, resulting in an arg1069-to-gln (R1069Q) substitution, that was found in compound heterozygous state in a patient with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0002.
In 6 patients from 4 unrelated families with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Paolacci et al. (2018) identified compound heterozygosity for 2 intronic variants, c.1909+22G-A (c.1909+22G-A, chr10.79769273, GRCh37) and c.3337-11T-C (c.3337-11T-C, chr10.79743781, GRCh37), on 1 allele of the POLR3A gene, and another mutation in POLR3A on the other allele. The patients comprised 1 (WRS002) of 2 sisters originally described by Rautenstrauch et al. (1977) (patient 'GM'), a 27-year-old Palestinian man and his 2 sibs (WRS004) who were reported by Akawi et al. (2013), a 21-year-old woman (WRS005) previously reported by Paolacci et al. (2017), and a German patient (WRS003). Analysis of RNA from patients WRS002 and WRS004 demonstrated that the c.1909+22G-A variant had a mild effect on exon 14 splicing, causing skipping of that exon and a frameshift resulting in a premature termination codon (Pro591MetfsTer9), whereas the c.3337-11T-C variant caused skipping of exon 26, resulting in an in-frame deletion (I1113_E1143del). In patient WRS002, the second mutation was another splice site mutation (c.1048+5G-T; 614258.0011) in intron 7 of the POLR3A gene, causing insertion of 177 bp of intronic sequence predicted to result in a frameshift and premature termination codon (Arg353ProfsTer24). The variant was present at very low frequency (0.0004%) in the gnomAD database. In the German patient (WRS003), the second mutation was a c.2474C-G transversion in the POLR3A gene, resulting in a ser825-to-ter (S825X; 614258.0012) substitution that was not found in the gnomAD database. In the 3 Palestinian sibs (WRS004), the second mutation was a c.1800C-T transition (614258.0013) within exon 14 of the POLR3A gene, a synonymous change that caused skipping of exon 14 with a frameshift resulting in a premature termination codon (Pro591MetfsTer9); this variant was not found in the gnomAD database. cDNA analysis showed a strong additive effect on splicing by the c.1800C-T and c.1909+22G-A mutations together, with increased skipping of exon 14 compared to c.1909+22G-A alone. In patient WRS005, the second mutation was another splice site mutation (c.2617-1G-A; 614258.0004), present at very low frequency (0.002%) in the gnomAD database. Paolacci et al. (2018) noted that the Palestinian sibs' apparently unaffected father was homozygous for the mutant allele carrying the c.1909+22G-A and c.3337-11T-C variants, indicating that this allele does not cause a phenotype in homozygous state; the authors suggested that a specific mutation signature indicated by the combination of compound heterozygous mutations in POLR3A is necessary to cause WDRTS. In addition, the authors stated that the c.1909+22G-A mutation represents a relatively common variant, present at a minor allele frequency of 0.1% in the gnomAD database, and noted that it previously had been reported without the presence of the c.3337-11T-C variant on the same allele in patients with leukodystrophy.
In a 20-year-old woman (subject 2) with WDRTS who was originally studied by Garg et al. (2015) (patient NLD 1300.4), and an unrelated 21-year-old woman (subject 6) with WDRTS, Wambach et al. (2018) reported compound heterozygosity for the c.3337-11T-C mutation (c.3337-11T-C, NM_007055.3) and another mutation in POLR3A: in subject 6, the second mutation was a splice site mutation (c.2617-1G-A; 614258.0004), and in subject 2, it was a c.2005C-T transition, resulting in an arg669-to-ter (R669X; 614258.0017) substitution. Analysis of RNA from subject 2 demonstrated that the c.3337-11T-C mutation caused skipping of exon 26; however, in contrast to the findings of Paolacci et al. (2018), Wambach et al. (2018) found that the c.1909+22G-A variant (c.1909+22G-A, NM_007055.3) did not result in exon skipping.
For discussion of the splicing mutation (c.1048+5G-T, chr10.79781613, GRCh37) in intron 7 of the POLR3A gene, causing insertion of 177 bp of intronic sequence predicted to result in a frameshift and premature termination codon (Arg353ProfsTer24), that was found in compound heterozygous state in a female patient (WRS002) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010.
For discussion of the c.2474C-G transversion (c.2474C-G, chr10.79760738, GRCh37) in the POLR3A gene, resulting in a ser825-to-ter (S825X) substitution, that was found in compound heterozygous state in a German patient (WRS003) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010.
For discussion of the c.1800C-T transition (c.1800C-T, chr10.79769404, GRCh37) in exon 14 of the POLR3A gene, resulting in a synonymous change (I600I) but shown to alter splicing and cause skipping of exon 14 with a frameshift resulting in a premature termination codon (Pro591MetfsTer9), that was found in compound heterozygous state in 3 Palestinian sibs (WRS004) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010.
In 2 unrelated patients (WRS008 and WRS009) from Colombia with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Paolacci et al. (2018) identified a c.Ter18C-T transition (c.Ter18C-T, chr10.79737218, GRCh37) in the POLR3A gene in compound heterozygosity with 2 different mutations. Patient WRS008, a male infant reported by Morales et al. (2009) as patient WRS2 and who died at 1 day of life, additionally carried a c.4003G-A transition, resulting in a gly1335-to-arg (G1335R; 614258.0016) substitution at a highly conserved residue. Patient WRS009, a 22-year-old man reported by Arboleda and Arboleda (2005), additionally carried a c.3G-T transversion (614258.0015), the effect of which on the protein was described by Paolacci et al. (2018) as M1?. All 3 variants were present at very low frequency (0.0004%) in the gnomAD database.
In a 5-year-old boy (subject 7) with WDRTS, Wambach et al. (2018) identified compound heterozygosity for the same 2 mutations identified in a 22-year-old Colombian man with WDRTS by Paolacci et al. (2018). Wambach et al. (2018) described the effect of the initiation codon mutation on the protein as M1X.
For discussion of the c.3G-T transversion (c.3G-T, NM_007055.3) in the POLR3A gene, resulting in a Met1-to-? (M1?) substitution, that was found in compound heterozygous state in patients with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018) and Wambach et al. (2018), see 614258.0014.
In an 11-month-old girl with WDRTS (patient 11), Lessel et al. (2018) identified heterozygosity for the c.3G-T (M1I) mutation. Although a second mutation was not detected, the authors suggested that it might be deeply intronic, a copy-number variant, balanced translocation, or possibly involve a regulatory region of POLR3A.
For discussion of the c.4003G-A transition (c.4003G-A, chr10.79739920, GRCh37) in the POLR3A gene, resulting in a gly1335-to-arg (G1335R) substitution, that was found in compound heterozygous state in a male infant (WRS008) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0014.
For discussion of the c.2005C-T transition (c.2005C-T, NM_007055.3) in the POLR3A gene, resulting in an arg669-to-ter (R669X) substitution, that was found in compound heterozygous state in a 20-year-old woman (subject 2) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Wambach et al. (2018), see 614258.0010.
In 4 unrelated children (subjects 1, 3, 4, and 5) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), including a 13-year-old girl (subject 3) previously studied by Garg et al. (2015) as patient NLD 2200.4, Wambach et al. (2018) identified compound heterozygosity for a c.3337-5T-A transversion (c.3337-5T-A, NM_007055.3) in intron 25 of the POLR3A gene and another splice site or truncating mutation in POLR3A. The c.3337-5T-A variant was present in only 1 heterozygous individual in gnomAD (minor allele frequency, 0.000004), and analysis of RNA from subject 1 showed that the mutation causes in-frame skipping of exon 26 (Ile1113_Glu1143del).
In a 10-year-old boy (patient 1) and an unrelated 12.75-year-old girl (patient 4) with WDRTS, Lessel et al. (2018) identified compound heterozygosity for the c.3337-5T-A splice site mutation and another mutation in the POLR3A gene: in the boy, the second mutation was a c.3337-1G-A variant (614258.0019) in intron 25, predicted to abolish the splice acceptor site, whereas in the girl it was a c.760C-T transition, resulting in an arg254-to-ter (R254X; 614258.0020) substitution. All 3 variants were extremely rare in the dbSNP, 1000 Genomes, ExAC, and gnomAD databases, and were only present in heterozygous state in those databases.
For discussion of the c.3337-1G-A transition in intron 25 of the POLR3A gene, predicted to abolish the splice acceptor site, that was found in compound heterozygosity in a 10-year-old boy (patient 1) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Lessel et al. (2018), see 614258.0018.
For discussion of the c.760C-T transition in the POLR3A gene, resulting in an arg254-to-ter (R254X) substitution, that was found in compound heterozygosity in a 12.75-year-old girl (patient 4) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Lessel et al. (2018), see 614258.0018.
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Joseph, C. G., Darrah, E., Shah, A. A., Skora, A. D., Casciola-Rosen, L. A., Wigley, F. M., Boin, F., Fava, A., Thoburn, C., Kinde, I., Jiao, Y., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Rosen, A. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343: 152-157, 2014. [PubMed: 24310608] [Full Text: https://doi.org/10.1126/science.1246886]
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